In wound treatment, active substances to cleanse the wound and promote healing thereof, for example, the enzyme mixture recovered from the culture filtrate Clostridium histolyticum and consisting of different collagenases, clostripain, and neutral proteases (in the following referred to as collagenase for reasons of simplicity), which must come into direct contact with the bottom of the wound to develop their action. Typically, these wound treatments are administered by means of administration forms which, owing to their consistency, may be applied without interruptions, even to very uneven surfaces. These administration forms include solutions, powders, dusts, and sprays, or semisolid preparations, such as ointments, creams, and gels.
Since the individual dosage is carried out by the user, the main disadvantage of these administration forms lies in the fact that an accurate, reproducible and even dosage of collagenase across the whole application surface is not possible, in particular if the application must be repeated. Moreover, the known administration forms entail further shortcomings. Solutions, powders, dusts, or sprays permit high utilization of the applied collagenase, i.e., the main portion of the administered collagenase takes effect in the wound, but they have the disadvantage that the collagenase can be controlled to an only very limited extent by the administration form. If, for example, a certain collagenase concentration is to be kept constant in the wound over a given period of time, a time-consuming treatment is required involving many quick-releasing single doses to be applied within relatively short intervals. Ointments and creams, however, offer much more possibilities of controlling the collagenase release and of prolonging the action, but, owing to their lipophilla, they have the disadvantage that the collagenase introduced into the wound is utilized to a comparatively small extent because large portions of the collagenase fail to diffuse to the interface to the wound within the application period, so that they cannot be released. With washing the ointment or cream out, this collagenase portion is removed without having taken effect at all.
The use of modern active substance carrier systems and active substance release systems, such as application systems in the form of a patch, which are not introduced into the wound, but are applied on the wound overlapping its edges, is out of the question for collagenase, because this enzyme mixture has a proteolytic action so that it may only get into the wound, but must not reach the wound edge or the intact skin around the wound.
It is accordingly the object of the present invention to find an administration form that has the advantages, but avoids the disadvantages of conventional administration forms in a wound treatment with collagenase, and which makes it possible to release collagenase to the bottom of the wound in an exactly, evenly and reproducibly dosed manner, even in case of repeated application.
Most surprisingly, this object has been found in a deformable, flat-shaped, collagenase-releasing administration form that is characterised by a combination of the following properties:
a. it is coherent, flat-shaped and deformable; PA1 b. it has a superficial extension that is equal to or smaller than the wound surface to be treated; PA1 c. it comprises collagenase in defined amounts in homogeneously distributed form; PA1 d. it is designed for the controlled release of collagenase. PA1 preservatives, such as p-CI-m-cresol, phenylethyl alcohol, phenoxyethyl alcohol, chlorobutanol, 4-hydroxybenzoic acid methylester, 4-hydroxybenzoic acid propylester, benzalkonium chloride, cetylpyridinium chloride, chlorohexidine diacetate or, digluconate, ethanol, or propylene glycol, PA1 pH-regulators, such as glycerol buffers, citrate buffers, borate buffers, phosphate buffers, or citric acid-phosphate buffers, PA1 antioxidants, such as ascorbic acid, ascorbylpalmitate, tocopherol acetate, propyl gallate, butylhydroxyanisole, or butylated hydroxytoluene, PA1 auxiliary agents to stabilize the biological activity of active substances, such as mannitol, glucose, lactose, fructose, saccharose, cyclodextrin, or dextran, PA1 emusifiable auxiliary agents, such as oils, fats, and waxes, PA1 emulsion stabilizers, such as non-ionogenic emulsifiers, amphoteric emulsifiers, cation-active emulsifiers, and anion-active emulsifiers, PA1 fillers, such as micro-crystalline cellulose, aluminum oxide, zinc oxide, titanium dioxide, talcum, silicon dioxide, magnesium silicate, magnesium aluminum silicate, kaolin, hydrophobic starch, calcium stearate, or calcium phosphate, PA1 foaming agents, such as saponins, alginic acid esters, amine oxides, or fatty amine oxides.